Treatment for Low Platelets

Alternative And Natural Therapies For Itp (idiopathic Thrombocytopenia Purpura). Live Free From Itp. Complete Program To Increase Platelets. This Is What You Will Learn With this Guide: The Two Herbs That can help bring up your platelets. The Two Vitamins needed to keep those platelets from dropping. What foods may cause your platelets to drop. How science has confirmed the benefits of these herbs in their use with low platelets. Why your doctor may not know about these natural alternatives and how you can assist him in helping you. Different tests that naturopathic doctors do to determine your real state of health that may reverse the course of your body drastically. Understand some of the reasons why people develop low platelets. Discover how your digestive tract may be the culprit to your low platelet level problems. How you can prevent the most drastic step a splenectomy. How you can restore your health so that you dont need any more dangerous drugs. Get your life back and stop ending up in the hospital all the time. Learn why your immune system is attacking your platelets and how to calm it down. Learn what over the counter medications to stay away from if you have low platelets Continue reading...

Who has recently received a red cell or platelet blood product. Treatment consists of steroids. Immunoglobulin is useful in severe cases. Rare patients may require plas-mapheresis. The patient's thrombocytopenia will resolve in a few months. If patients with a history of PTP require further transfusions the red cells should be washed and only PLA1 negative platelets should be given. Heparin-induced thrombocytopenia (HIT) Heparin can induce a unique form of immune thrombocytopenia. Unfortunately, some of these patients will then develop severe thrombosis. HIT is discussed in more detail in Chapter 22.

The distinction between thrombocytopenia that begins early (within 4 days) or late (5 or more days after beginning heparin treatment) is a simple clinical feature that is useful to distinguish nonimmune HAT, which begins early, from (immune) HIT, which begins late. For this assessment, the first day of heparin use is considered day 0. There is an important exception to this rule of timing for HIT a rapid fall in platelet count on starting heparin therapy can represent acute HIT, but only if a patient already has circulating HIT antibodies, usually the result of a recent heparin exposure. HIT antibodies are transient, which could explain why the risk for rapid-onset HIT is restricted to a period of about 100 days following exposure to heparin (Warkentin and Kelton, 2001) (see Chapter 2). Typically, nonimmune HAT begins 1 -2 days after starting heparin administration and resolves during continued heparin therapy (Johnson et al., 1984 Chong and Berndt, 1989 Warkentin and Kelton, 1994...

Practically, these findings suggest strategies for platelet count monitoring in patients receiving heparin. Some physicians are hesitant to institute regular platelet count monitoring for HIT. One explanation is the almost ubiquitous use of heparin in hospitalized patients. Thus, a requirement that regular, perhaps even daily, platelet count monitoring be performed seems excessive. Additionally, there is no convincing evidence that regular platelet count monitoring can prevent the throm-botic complications of HIT if the physician response is merely to stop the heparin (Wallis et al., 1999). However, a noteworthy consideration is that instituting alternative, parenteral anticoagulation likely will prevent thrombosis in patients recognized as having isolated HIT. These comments notwithstanding, marked differences in risk for HIT are apparent among different patient populations. Thus, it seems prudent to recommend that patients at the highest risk of HIT, and for HIT-associated...

Nonimmune heparin-associated thrombocytopenia (HAT) describes the common clinical situation in which a patient develops a fall in platelet count within the first few days of receiving heparin. Often, there are concomitant clinical factors to explain the thrombocytopenia (e.g., hemodilution, bacteremia, or disseminated intravascular coagulation DIC ). In some patients, however, it is possible that a direct proaggregatory effect of heparin is responsible for the drop in platelet count (Salzman et al., 1980). The designation associated helps to convey the uncertain role of heparin in causing thrombocytopenia in this setting, and the term nonimmune distinguishes this syndrome from immune-mediated HIT (Warkentin et al., 1998). Nonimmune HAT is typically mild, often transient, and clinically inconsequential (Gollub and Ulin, 1962 Johnson et al., 1984 Chong, 1988 Warkentin and Kelton, 1994). There is debate whether this represents a real in vivo phenomenon or whether the apparent...

Amegakaryocytic thrombocytopenia Carbamazepine Alcohol Sequestration Post-transfusion purpura Heparin-induced thrombocytopenia Non-immune destruction Rare patients with autoimmune amegakaryocytic thrombocytopenia may present with severe thrombocytopenia but do not respond to steroids or immunoglobulin. On marrow biopsy they have diminished to absent megakaryocytes. The etiology is due to suppressor T-cells repressing platelet production. Therapy is with cyclosporine or anti-thymocyte globulin. In elderly patients, mild thrombocytopenia may be the first indicator of a myelodysplastic syndrome. Patients with myelodysplasia usually have an elevated MCV even if anemia is absent.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increases the platelet count in HIV-infected baboons. Three thrombocytopenic, HIV-infected baboons were treated with three doses of PEG-rHuMGDF (arrows), and the platelet count was measured. (Reproduced with permission from ref. 96.) Fig. 10. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increases the platelet count in HIV-infected baboons. Three thrombocytopenic, HIV-infected baboons were treated with three doses of PEG-rHuMGDF (arrows), and the platelet count was measured. (Reproduced with permission from ref. 96.)

PEG-rHuMGDF has been given to healthy volunteers (99) and healthy apheresis donors (100-102). Treatment of apheresis donors with a single dose of PEG-rHuMGDF on d 1 produces a dose-dependent increase in the platelet count that begins on d 5 and peaks after 10-12 d (Fig. 11). A clear dose-response effect is seen. Compared with placebo-treated donors who had platelet counts of 225 x 109 L, donors treated with 1 or 3 g kg of PEG-rHuMGDF had median platelet counts of 336 x 109 L and 599 x 109 L, respectively. The donors experienced no adverse effects. The platelets produced had normal platelet aggregation responses in vitro and, when transfused into thrombocytopenic recipients, produced a dose-dependent increase in platelet count (101).

We will discuss the diagnostic approach to HIT based on the timing of onset of thrombocytopenia, either rapid (&lt 5 days) or typical (&gt 5 days) (see Chapter 2). In general, there are two broad pretest probabilities for patients with rapid thrombocytopenia low and high. Patients with low pretest probability for HIT are those who have not recently been exposed to heparin (thus, they would not be expected to have circulating HIT antibodies, or to have generated them so quickly), or who have another good explanation for thrombocytopenia. (An important caveat is that sometimes a recent heparin exposure is not known to the patient or has not been documented in the medical records.) With a low pretest probability for HIT, either of the sensitive assays for HIT (washed platelet activation assay or antigen assay) can reliably rule out HIT. However, an unexpected negative result in a patient with a high pretest probability, or an unexpected positive result in a patient with a low pretest...

Glycoprotein (GP) IIb IIIa antagonists (abciximab, tirofiban, eptifibatide) are used during coronary angioplasty to reduce platelet-mediated thrombosis. However, in a few patients ( 1 ), acute thrombocytopenia begins within hours of GPIIb IIIa antagonist use (Aster et al., 2006 Warkentin, 2007). The thrombocytopenia is typically severe (usually &lt 20 X 109 L) and life-threatening bleeding can sometimes occur. Interestingly, most reported cases have occurred after first exposure to one of these drugs, although the frequency may be higher with repeat exposures (especially with abciximab) (Curtis et al., 2002). Platelet counts usually recover in 2-5 days after discontinuing the drug. Thrombocytopenia occurring after first exposure to a GPIIb IIIa antagonist is explained by naturally occurring antibodies that recognize GPIIb IIIa in the presence of the provoking drug (Bougie et al., 2002). Delayed onset of thrombocytopenia is explained by persistence of platelet-bound drug for several...

In some patients, especially those with comorbid conditions associated with platelet activation (burns and anorexia nervosa), heparin treatment can result in a transient decrease in platelet count (Burgess and Chong, 1997 Reininger et al., 1996) (see Chapter 4). Unfractionated heparin (UFH) activates platelets directly (Salzman et al., 1980), an effect observed less frequently with low molecular weight heparin (LMWH) (Brace and Fareed, 1990). Known as nonimmune heparin-associated thrombocytopenia (nonimmune HAT), this direct proaggregatory effect of heparin occurs predominantly in patients receiving high-dose, intravenous (iv) UFH therapy. Typically, platelet counts decrease within the first 1-2 days of treatment and then recover over the next 3-4 days. There are no data indicating that these patients are at increased risk for adverse outcomes, including thrombosis. Indeed, it is possible that inappropriate discontinuation of heparin for nonimmune HAT could increase the risk for...

Three prospective studies with lepirudin for HIT were designated heparin-asso-ciated thrombocytopenia (HAT)-l, -2, and -3 (Greinacher et al., 1999a,b, 2000 Lubenow and Greinacher, 2002 Lubenow et al., 2005). There was no approved non-heparin alternative anticoagulant during the 3 yr in which the HAT studies were conducted (March 1994-April 1996), and thus for ethical reasons, a placebo control was not appropriate. The HAT studies therefore included comparisons of clinical outcomes with a historical control group treated before lepirudin became available. A meta-analysis of HAT-1 and -2 was performed to evaluate patients given lepirudin for treatment of HIT with thrombosis (Greinacher et al., 2000). A second meta-analysis of the HAT-1, -2, and -3 studies was performed to evaluate the effects of lepirudin in patients with HIT and isolated thrombocytopenia (isolated HIT) (Lubenow et al., 2004). In addition, an observational study termed the drug-monitoring program (DMP) was carried out...

Thrombocytopenia OTher cause for thrombocytopenia Patients with HIT but without evidence of thrombosis are at a high risk of thrombosis (53 in one study) and should be considered for antithrombotic therapy. Patients with HIT should also be carefully screened for any thrombosis, which includes obtaining lower extremity dopplers. It is unknown whether prophylactic doses or therapeutic doses of anticoagulants are needed for thrombosis prevention in patients with HIT but no thrombosis. The duration of such therapy is also controversial. One approach is to give prophylactic doses of antithrombotic agents until the platelet count has returned to normal. In post-surgical patients prolonged prophylaxis for up to six weeks may be of benefit. 8. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-in-duced thrombocytopenia. Arch Pathol Lab Med 2002 126(11) 1413-23. 10. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol...

Monitoring for typical-onset HIT stratifying the intensity of platelet count monitoring for HIT based upon its risk C. Patients at low risk for HIT (&lt 0.1 ) (e.g., medical obstetrical patients receiving prophylactic- or therapeutic-dose LMWH, or medical patients receiving only intravascular catheter flushes with UFH) routine platelet count monitoring is not recommendedd 2. Monitoring for rapid-onset HIT for a patient recently exposed to heparin (within the past 100 days), a repeat platelet count within 24 h following reinitiation of heparin A relative (proportional) platelet count fall of 50 or greater that is otherwise clinically unexplained should be considered suspicious for HIT, even if the platelet count nadir remains above 150x109 L. For any patient who develops thrombosis during (day 5 to 14) or within several days after stopping heparin therapy, or who develops an unusual clinical event in association with heparin therapy (e.g., inflammatory or necrotic skin lesions at...

Heparin-induced thrombocytopenia (HIT) is strongly associated with life- and limb-threatening venous and arterial thrombosis, including pulmonary embolism, venous limb gangrene, and large vessel arterial occlusion. However, HIT is by no means a unique explanation for the combination of thrombocytopenia and thrombosis (Table 1). In these pseudo-HIT disorders so named because they strongly mimic HIT on clinical grounds thrombocytopenia usually occurs early during the course of heparin treatment. This could reflect the prothrombotic process associated with the patient's primary diagnosis. Alternatively, heparin could exacerbate the platelet count fall by nonimmune proaggregatory effects on platelets (see Chapter 4). If the patient previously received heparin, physicians might consider HIT in the differential diagnosis of the platelet count fall. However, one pseudo-HIT syndrome in particular closely resembles even the typical day 5-10 timing of thrombocytopenia characteristic of HIT...

Heparin-Induced Thrombocytopenia Routine platelet count measurements were not a feature of hospital laboratory practice until the 1970s, and neither the Dartmouth nor Philadelphia surgeons reported thrombocytopenia in their patients with heparin-induced arterial thrombosis. Ironically, the first report of severe heparin-induced thrombocytopenia (HIT) involved a patient who did not develop paradoxical thrombosis. Natelson and coworkers (1969) reported on a 78-yr-old man with prostate carcinoma and pulmonary embolism, who on day 10 of treatment with therapeutic-dose heparin developed severe thrombocytopenia. Three days after discontinuing the heparin therapy, the patient's fibrinogen fell to 1 g L, attributed to carcinoma-associated disseminated intravascular coagulation (DIC). Heparin treatment was restarted and, although fibrinogen levels normalized, the platelet count fell to 5 X 109 L, rising to 115 X 109 L 6 days after stopping heparin administration. Simultaneously, however,...

In retrospective studies, Auger and colleagues (1995) reported that platelet counts typically fell by about 50 in patients with chronic thromboembolic disease and the lupus anticoagulant who were treated with heparin. Neither timing of the onset of thrombocytopenia nor results of specific antigen or activation assays for HIT antibodies were reported so it remains uncertain whether these patients had (immune) HIT. It is possible that nonidiosyncratic platelet activation caused by heparin could increase the thrombocytopenic potential of antiphospholipid antibodies in the absence of HIT antibodies. Alternatively, some patients with APLAS may have low levels of circulating HIT antibodies even in the absence of previous heparin exposure (Lasne et al., 1997 Martinuzzo et al., 1999). We observed a young woman with ischemic stroke who developed thrombocytopenia and lower-limb thrombosis when therapeutic-dose heparin was given pretreatment blood samples contained both antiphospholipid...

Given the major role of unfractionated heparin (UFH) for anticoagulation in hemodialysis (HD), it is important to define the potential impact of immune heparin-induced thrombocytopenia (HIT) in contributing to morbidity and mortality in patients with dialysis-dependent renal failure. To date, there is only one study reporting the incidence of HIT in patients being newly treated with HD. Six of 154 patients (3.9 ) were clinically suspected of having developed HIT because of a fall in the platelet count accompanied by clotting of the dialyzer and extracorporeal circuit (Yamamoto et al., 1996). The clinical diagnosis was confirmed by the detection of HIT antibodies in all but one patient. Only one patient developed organ damage from thrombosis (myocardial infarction and stroke). All six patients were switched to an alternative anticoagulant and did not suffer from thromboembolic events in the follow-up period. Compared with the incidence of HIT of 2.7 found in 332 hip surgery patients...

Nonimmune Mechanisms in Heparin-Associated Thrombocytopenia Klein and Bell (1974) reported on two patients who developed severe thrombocytopenia, thrombotic complications, and DIC, with hypofibrinogenemia and microangiopathic red cell abnormalities i.e., these patients likely had severe HIT. This experience prompted Bell to perform the first prospective study investigating the frequency of thrombocytopenia complicating therapeutic-dose UFH (Bell et al., 1976). Sixteen of 52 patients (31 ) developed a platelet count fall to less than 100 x 109 L, and some of these patients developed hypofibrinogenemia and elevated fibrin(ogen) degradation products. The authors speculated that a thromboplastic contaminant extracted along with heparin from beef lung could explain the thrombocytopenia. A subsequent randomized controlled trial by Bell and Royall (1980) found the frequency of thrombocytopenia to be higher in patients who received bovine heparin (26 ) compared with heparin of porcine...

Thrombocytopenia is a relatively common finding in hospitalized patients. For example, thrombocytopenia is very common in the critical care population, with platelet counts below 100,000 L found in 25-38 of such patients. Finding the etiology is frustrating, as multiple factors may be producing the thrombocytopenia. A rational approach is to consider the differential from a mechanistic point of view. Thus defects in platelet production, increased platelet sequestration, or increased platelet destruction (immune or non-immune) can lead to thrombocytopenia. The mode of presentation can be an important clue to the etiology of the throm-bocytopenia . Patients who present only with severe thrombocytopenia and no other systemic signs or symptoms (outside of bleeding) and a normal blood smear most often will have either idiopathic or drug-induced immune thrombocytopenia. If the patient is in the hospital, the reason for hospitalization is a very important indicator in the evaluation of...

Other patients have developed skin lesions during intravenous heparin therapy, or at locations otherwise distant from subcutaneous injection sites, in the absence of coumarin therapy. Hartman and colleagues (1988) reported a man who received intravenous heparin for saphenous vein thrombosis the platelet count fell from 864 to 44 X 109 L (day 10). On day 7, when the platelet count had fallen by 33 to 575 X 109 L, progressive necrosis of skin in the thigh at the region of the thrombosed vein occurred, necessitating surgical excision. Thrombosis of veins and capillaries, with arterial sparing, was noted. Balestra et al. (1994) reported a patient who developed thrombocytopenia (75 X 109 L) and skin necrosis of the thigh on day 9 of subcutaneous injections of LMWH given into the lower abdominal wall. A skin biopsy showed small vessel thrombosis with a mild inflammatory reaction. Other clinicians have reported patients with HIT antibodies who developed skin lesions that occurred at...

Various scoring systems to estimate the probability of HIT based upon clinical information have been published, usually for the purpose of evaluating new laboratory tests for HIT (Greinacher et al., 1994 Pouplard et al., 1999 Alberio et al., 2003). These systems have included the platelet count recovery following heparin cessation, which limits their applicability for judging the clinical likelihood of HIT in real time when a thrombocytopenic patient receiving heparin is first evaluated. Further, these scoring systems were developed before various features of the timing and severity of platelet count fall in HIT were understood.

Tables 2 and 3 list prospective studies of the frequency of HIT that employed in vitro testing for HIT antibodies or were studies in which the likelihood of HIT could be judged based on information provided, especially the timing of the onset of thrombocytopenia. Relevant variables influencing the frequency of HIT include the type of heparin used and the patient population. TABLE 2 The Frequency of HIT Prospective Studies of HIT in Medical Patients Using In Vitro Testing of Patient Serum Plasma for HIT Antibodies or Indicating a High Likelihood of HIT Based on Timing of Platelet Count Fall TABLE 2 The Frequency of HIT Prospective Studies of HIT in Medical Patients Using In Vitro Testing of Patient Serum Plasma for HIT Antibodies or Indicating a High Likelihood of HIT Based on Timing of Platelet Count Fall

In contrast, HIT may occur more often in prospective studies of acute HD patients receiving porcine UFH (Yamamoto et al., 1996). Whether this is a real difference that reflects increased platelet activation (and PF4 release) during HD or it reflects a more sensitive definition of thrombocytopenia (any platelet count fall associated with line clotting) is unknown. The frequency of clinical HIT in chronic HD patients appears to be less than 2 and may be considerably lower, but up to 18 develop a positive EIA for anti-PF4 heparin antibodies. Whether the incidence of elevated levels of anti-PF4 heparin antibodies and clinical HIT are dependent on the time since the initiation of HD is unclear. Some have suggested that the frequency of anti-PF4 heparin antibody increases with time (Palomo et al., 2005), while others have found no association (Pe a de la Vega et al., 2005). Two studies suggest that the antibodies tend to develop early after initiation of HD, and may disappear after months,...

Although there have been several RCTs evaluating the efficacy of LMWH for prophylaxis in medical patients, published descriptions of secondary safety endpoints such as HIT are usually brief and often inadequate to judge whether the occurrences of thrombocytopenia were due to HIT or not (Samama et al., 1999 Turpie, 2000 Leizorovicz et al., 2004). In one RCT of prophylactic-dose LMWH (enoxaparin) versus UFH in medical patients, no cases of new onset of thrombocy-topenia (platelet count &lt 100 x 109 L) were observed in 216 patients randomized to receive LMWH (Bergmann and Neuhart, 1996). In another RCT that compared deep-vein thrombosis treatment with LMWH (reviparin) versus UFH, none of 720 patients who received LMWH developed (antibody-positive) HIT, whereas one of 356 (0.3 ) patients treated with UFH manifest this complication (Lindhoff-Last et al., 2002). Interestingly, if the definition of HIT in that study was expanded to include thrombosis and a positive test for anti-PF4 heparin...

Two large prospective studies suggest that HIT is an important problem in orthopedic patients receiving UFH (Warkentin et al., 1995, 2003, 2005a Greinacher et al., 2005a). When using a proportional fall in platelet count (e.g., 50 or greater) that began on or after day 5 of heparin treatment, and that was confirmed by serologic testing for HIT antibodies, both studies observed a frequency of HIT of about 5 (Table 3). Each study used porcine mucosal heparin, derived from a different manufacturer, given by the subcutaneous (sc) route at a dosage of 15,000 U day. Other studies of postorthopedic UFH thromboprophylaxis (using confirmatory in vitro testing) have shown frequencies of HIT of about 2.0 (Leyvraz et al., 1991 Mahlfeld et al., 2002).

The strongest evidence that LMWH is indeed associated with a lower frequency of HIT was provided by an RCT that directly compared the frequency of HIT between the two types of heparin (Warkentin et al., 1995, 2003, 2005a). The frequency of HIT in patients treated with the LMWH preparation, enoxaparin (itself derived from porcine mucosal heparin), was lower than that seen in patients treated with porcine UFH, irrespective of whether a standard definition (platelet fall to &lt 150 x 109 L on or after day 5 of heparin treatment) or a more sensitive definition (&gt 50 platelet count fall from the postoperative peak) of thrombocyto-penia was used. The frequency of HIT antibody formation also differed between the two patient groups, using either the SRA (Warkentin et al., 1995, 2005a) or a PF4 heparin (or PF4 polyanion) EIA (Warkentin et al., 2000, 2005a). Thrombocytopenia also appeared to be infrequent in other trials of LMWH (Leyvraz et al., 1991 Simonneau et al., 1997 ENOXACAN Study...

Thrombocytopenia is common in critically-ilL patients, occurring in up to half of all patients in the intensive care unit (ICU). In this population, the presence of thrombo-cytopenia is associated with increased mortality, and depending on severity and etiology, is associated with increased hemorrhagic risk as well. ICU patients often have several potential causes of thrombocytopenia, making evaluation challenging. Heparin exposure (in the form of line flushes, prophylaxis, or therapeutic anticoagulation) is virtually ubiquitous in the ICU, making HIT a frequent diagnostic consideration. There have been several prospective and retrospective studies that have evaluated the frequency of HIT in critically ill patients (Table 4). The two largest prospective studies (Verma et al., 2003 Crowther et al., 2005) found that although HIT was clinically suspected in 12 to 15 of ICU patients, compatible serology supporting the diagnosis (including the washed platelet activation assay, a relatively...

Ventricular assist devices (VADs) are surgically implanted mechanical pumps that have a large foreign surface area in direct contact with flowing blood, thereby creating an inherently prothrombotic environment. In a non-randomized study of patients who received heparin-coated and uncoated VADs, there was no difference in the development of anti-PF4 heparin antibodies and thromboembolism between the groups (Koster et al., 2001). In two more recent studies, 10 113 (8.8 ) (Schenk et al., 2006, 2007) and 28 358 (7.8 ) (Koster et al., 2007) of VAD patients developed apparent HIT. In both studies, the frequency of anti-PF4 heparin antibody formation (by EIA) was over 60 . While these apparent frequencies of clinical HIT ( 8 ) are among the highest reported in any patient population, it remains unclear how to distinguish true clinical HIT from a patient with cardio-genic shock or other non-HIT explanations for thrombocytopenia who coinciden-tally develop heparin-dependent platelet-activating...

As HIT typically begins 5-10 days after starting therapy with heparin, it follows that the length of heparin treatment can influence the risk for HIT, e.g., a 10-14 day course of UFH is far more likely to result in clinical HIT than a 1 day treatment period (&gt 2 vs. 0.02 , i.e., an OR of 100). Of note, there is evidence that the risk of HIT begins to decline after 10 days of uninterrupted heparin use (see Fig. 1C, Chapter 2). In a large study of postoperative orthopedic surgical patients receiving postoperative heparin prophylaxis, no patient developed HIT antibodies after day 10, even though many patients received heparin for up to 14 days (Warkentin et al., 1995). These data are consistent with a point exposure model for risk of HIT in this patient population, such as a brief time shortly after surgery, when high circulating PF4 levels coincide with the first few sc heparin injections. However, even if HIT antibody formation occurs during the day 5-10 window period,...

It is possible that nonthrombotic mortality may be higher than expected by chance in patients with HIT. This speculation is based on the observation that only a minority of patients who form anti-PF4 heparin antibodies develop HIT (discussed subsequently) a corollary to this statement is that comorbid factors that tend to result in increased pathogenicity of heparin-dependent antibodies may also independently contribute to increased patient morbidity and mortality (i.e., patients with septicemia or multisystem organ failure may be more likely to have platelet activation in the presence of HIT antibodies than well patients). Alternatively, because the patients develop thrombocytopenia they are tested for heparin-dependent antibodies, and non-pathogenic antibodies are detected.

Isolated HIT is defined as the initial recognition of HIT because of thrombocytopenia alone, rather than because symptoms or signs of thrombosis draw attention to the possibility of underlying HIT. A large retrospective cohort study (Warkentin and Kelton, 1996) suggests that the subsequent frequency of new, progressive, or recurrent thrombosis is relatively high in such a patient population with serologically confirmed HIT (Fig. 2). Although these data are retrospective, the investigators attempted to minimize bias. First, the date that the HIT assay was ordered was used as an objective marker of first suspicion of the diagnosis of HIT. Second, patients were excluded from analysis if there was any evidence in the medical records to suggest the possibility of new signs or symptoms of thrombosis that may have caused the physician to suspect HIT. In other words, efforts were made to identify patients in whom HIT was suggested because of thrombocytopenia alone. Finally, only objectively...

Usually, serological investigation for HIT antibodies is performed on patients who develop thrombocytopenia during heparin treatment. Since 1995, however, many studies have systematically assessed heparin-dependent antibody seroconversion 3. Seroconversion occurs frequently without thrombocytopenia or thrombosis. Indeed, most patients who form HIT antibodies do not develop HIT. The proportion who develop HIT, however, is highest among the patients who have a positive SRA. This suggests that HIT antibodies strong enough to activate platelets are more likely to be clinically significant. Patient-dependent factors also must be important, however, because the probability of a positive SRA indicating clinical HIT ranges from about &lt 10 (cardiac surgery) to approximately 50 (orthopedic surgery patients receiving UFH).

Once stimulated by exposure to PF4-heparin, HIT antibodies can bind to PF4 complexed with other GAGs (e.g., heparan sulfate and chondroitin sulfate) on cell membranes. By this mechanism, they could stimulate platelets (Rauova et al., 2006) and also (directly or indirectly) endothelial expression of tissue factor (Cines et al., 1987 Herbert et al., 1998). Such heparin-independent binding of HIT antibodies to platelets and endothelium may explain the appearance or persistence of thrombocytopenia in HIT after heparin exposure has ceased (see Chapter 2). Activation of platelets in the absence of heparin, however, appears to require extensive saturation of the platelet surface with PF4, since antibody binding in vitro is observed only with PF4 concentrations &gt 300 nM, whereas the Kd for the binding of PF4 to platelets is reported to be about 30 nM (Loscalzo et al., 1985 Rauova et al., 2006). Such concentrations would be rarely, if ever, achieved in vivo. On the other hand, PF4 binds to...

Preexisting antibodies to chemokines, such as IL-8 or NAP-2, or possibly even to PF4 itself, may be present in some patients before heparin therapy (Sylvester et al., 1992 Bendtzen et al., 1995 Warkentin et al., 2006b). These antibodies may occur naturally or be induced in pathologic states, where they might have a regulatory role in inflammation (Reitamo et al., 1993). In some diseases, they are present at high concentrations. Antibodies to IL-8 are the most common (Reitamo et al., 1993). However, in some patients, true autoantibodies to PF4 alone can also be observed. In the absence of heparin, these antibodies usually do not demonstrate any clear pathogenicity. However, during heparin therapy, PF4 and other chemo-kines are released into blood from their storage pools. Heparin may further localize these chemokines onto blood cells and endothelium, with deleterious consequences. The amount of chemokine-heparin complexes bound to blood cells and ECs depends on different factors the...

In addition to platelet and endothelial cell activation, there is concomitant activation of coagulation, as shown by marked elevations in thrombin-AT complex levels (Warkentin et al., 1997 Greinacher et al., 2000). The simultaneous activation of platelets, endothelium, and coagulation factors is in line with the development of thrombocytopenia combined with thrombosis and disseminated intravascular coagulation in patients with HIT (see Chapter 2).

There are at least two potential explanations for strong platelet activation in the absence of added heparin. First, there may be residual heparin in the sample (White et al., 1992 Potzsch et al., 1996). However, this phenomenon can persist despite attempts to remove heparin using binding resins. Further, heparin-independent platelet activation can be a feature of serum obtained from patients with delayed-onset HIT, in which the presence of residual heparin is unlikely because onset of thrombocytopenia and thrombosis begins several days after the patient's last exposure to heparin (Warkentin and Kelton, 2001) (see Chapter 2). A second explanation is that some HIT antibodies recognize platelet-bound PF4 in the absence of an exogenous source of heparin, perhaps by PF4 bound to platelet glycosaminoglycans such as chondroitin sulfate (Rauova et al., 2006). Alternatively, as HIT antibodies are heterogeneous, there may be pathogenic antibody subpopulations that bind relatively well to PF4...

Detecting HIT antibodies not associated with thrombocytopenia or other clinical events (Amiral et al., 1995 Arepally et al., 1995 Bauer et al., 1997 Warkentin et al., 2000, 2005a Juhl et al., 2006 Schenk et al., 2006, 2007) (Fig. 6). Stated another way, the SRA is more specific for clinical HIT than the antigen assay. The biological explanation for greater specificity of a sensitive activation assay for clinical HIT, compared with an antigen assay, could relate to the functional heterogeneity of HIT antibodies against antigenic determinants on PF4, only some of which activate platelets strongly (Amiral et al., 2000). Data reported by Visentin and colleagues (1994) also support a higher sensitivity of antigen assays for detecting platelet-activating anti-PF4 H antibodies. These workers studied 12 HIT plasmas that tested positive in both SRA and PF4-heparin-EIA. However, at a 1 100 sample dilution, only 2 of the 12 samples still tested positive in the activation assay. In contrast, even...

In patients with a high pretest probability of HIT who have a negative screening test, the test should be repeated and the complementary activation or antigen assay should be performed. The diagnosis of HIT is very unlikely if both activation and antigen assays are negative. In patients with a moderate pretest probability who have one or more positive tests for HIT, the final diagnosis may well rest on the overall clinical picture, rather than on the test result alone. This conclusion results from two clinical realities (1) sensitive HIT assays frequently detect clinically insignificant anti-PF4-H antibodies in patients who have received heparin for more than 5 days, and (2) thrombocytopenia, whether caused by HIT or not, is common in clinical practice. There is evidence that positive washed platelet activation assays for HIT have greater diagnostic specificity for clinical HIT (Warkentin et al., 2000, 2005a), especially when strong, rapid platelet activation is produced by patient...

FIGURE 4 Pseudo-HIT associated with PE versus HIT (A) A patient developed a platelet count fall from 387 to 159x 109 L (59 fall) that began on day 7 of UFH prophylaxis following orthopedic surgery. PE was diagnosed by pulmonary angiography on postoperative day 11. The platelet count fell during initial intravenous heparin therapy, rising only when sufficient UFH was given (2360 U h) to overcome heparin resistance (as shown by subtherapeutic activated partial thromboplastin times, aPTTs). HIT antibodies were not detectable (day 12), either by SRA, (&lt 5 release) or PF4-heparin-EIA (optical density, 0.149 negative, &lt 0.450). (B) A platelet count profile similar to that seen in (A) also occurred in a patient who developed a platelet count fall from 378 to 161 x 109 L (57 fall) that began on day 7 after cardiac surgery in which UFH was given for CPB. The platelet count recovered on therapeutic-dose danaparoid. Only one clinical clue pointed to the diagnosis of HIT erythematous skin...

Early-onset thrombocytopenia occurs in about 1 of patients with acute coronary syndrome whether treated by heparin or non-heparin anticoagulants (Eikelboom et al., 2001). The frequency of thrombocytopenia is even higher in patients treated with streptokinase, especially when this thrombolytic agent is combined with heparin (Balduini et al., 1993) (Fig. 6). This could represent a direct, activating stimulus of heparin on platelets that perhaps is exacerbated by procoagulant FIGURE 6 Pseudo-HIT associated with thrombolytic therapy. A 72-yr-old man developed moderate thrombocytopenia shortly after receiving streptokinase and heparin, which resolved following discontinuation of heparin. The early onset of thrombocytopenia, as well as the negative testing for HIT-IgG using the platelet serotonin-release assay, was consistent with pseudo-HIT. Abbreviations HIT, heparin-induced thrombocytopenia i.v., intravenous p.o., per os s.c., subcutaneous. Source From Warkentin and Kelton, 1994. FIGURE...

Only a small minority of septic patients develop acral limb ischemia or necrosis. Many, however, develop thrombocytopenia, with or without laboratory evidence for DIC. The predominant explanation for increased platelet destruction in sepsis is uncertain, but appears to involve the underlying inflammatory host response (Aird, 2003a,b). Since hospitalized septic patients frequently are exposed to heparin, diagnostic confusion with HIT can result. Low protein C levels correlate with poor outcomes in sepsis (Yan et al., 2001), and recombinant human activated protein C (drotrecogin, Xigris) has been shown to reduce mortality in septic patients (Bernard et al., 2001). It is possible that this therapy might reduce risk of limb ischemia from microvascular thrombosis in this patient population. A potential dilemma is that septic patients with severe thrombocytopenia (&lt 30 X 109 L) were excluded in the clinical trials because of the bleeding potential of drotrecogin however, as relative and...

Infective endocarditis is frequently complicated by thrombocytopenia. These patients are also at risk for septic emboli manifesting as thrombotic or hemorrhagic stroke, myocardial infarction, renal infarction, or even acute limb ischemia (de Gennes et al., 1990). Thus, the profile of macrovascular thrombosis and thrombocy-topenia characteristic of HIT can be mimicked, especially as heparin is often used to anticoagulate patients with septic endocarditis (Delahaye et al., 1990). Micro-embolization leading to multiple small infarcts or microabscesses, in such organs as muscles, adrenal glands, and spleen, is an additional feature of endocarditis (Ting et al., 1990) that is not seen in HIT. When endocarditis-associated thrombocytope-nia is unusually severe, potential explanations include platelet-reactive autoantibo-dies (Arnold et al., 2004) or procoagulant monocyte-stimulating factors secreted by microorganisms from within large vegetations (Selleng et al., 2006).

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal myeloid disorder characterized by an acquired defect in the X-linked phosphatidylinositol glycan class A (PIG-A) gene, leading to loss of cell surface glycosylphosphatidylinositol-anchored proteins (for review see Rosse, 1997). Loss of the complement-regulating glycosylphosphatidylinositol-linked surface proteins, decay-accelerating factor and membrane attack complex inhibitory factor, causes the red cells to be exquisitely sensitive to complement-mediated hemolysis. Some patients have thrombocytope-nia, and an increased risk for unusual, life-threatening venous thrombotic events, such as hepatic vein thrombosis, occurs in some patients. Thus, the clinical profile of HIT potentially can be mimicked. The thrombocytopenia could be related either to decreased platelet production or to complement-mediated formation of procoagulant platelet-derived microparticles (Wiedmer et al., 1993).

Because both PTP and HIT typically occur about a week after surgery managed with perioperative blood transfusions and postoperative heparin prophylaxis, a diagnostic dilemma can arise (Lubenow et al., 2000). A useful clinical clue is the presence or absence of petechiae PTP almost invariably is characterized by this hallmark of severe thrombocytopenia, whereas patients with HIT generally do not develop petechiae, even if they have very severe thrombocytopenia. The presence of high titers of platelet-reactive alloantibodies suggests PTP.

Many patients with pseudo-HIT can be distinguished from HIT because of the early onset of thrombocytopenia (Table 1). Unless the patient received heparin within the past 30, and at most 100, days, the early platelet count fall is the strong evidence against HIT (Warkentin and Kelton, 2001 Lubenow et al., 2002) (see Chapter 2). However, for patients with adenocarcinoma-associated DIC, or postoperative pulmonary embolism, in whom the platelet count fall can occur after 5 days of heparin treatment, the diagnosis initially could be uncertain. As alternative anticoagulants (danaparoid, lepirudin, or argatroban) are available in most countries, treatment with one of these agents before obtaining results of HIT antibody testing may be appropriate. For patients with adenocarcinoma without HIT antibodies, management is more successful with LMWH or UFH than with warfarin (Prandoni, 1997 Lee et al., 2003). FIGURE 7 Pseudo-HIT complicated by HIT A 78-yr-old man, with right proximal lower-limb DVT...

An increasingly recognized treatment issue involves patients with detectable anti-PF4 heparin antibodies but no platelet count reduction or other clinical evidence of HIT. With increased testing for HIT antibodies, it is now clear that many patients develop anti-PF4 heparin antibodies without developing clinical HIT (see Chapters 3 and 10). In these patients, it seems acceptable to continue heparin treatment but to monitor the platelet counts carefully (watch-and-wait strategy).

Numerous case reports describe the occurrence of new, progressive, or recurrent thromboembolic events during continued or repeated use of heparin in patients with acute HIT. Moreover, the thrombocytopenia usually persists if the administration of heparin is not stopped. Thus, all heparin treatment should be discontinued in patients strongly suspected of having HIT and usually substituted by another anticoagulant (discussed subsequently), while awaiting results of HIT antibody testing. The rationale behind substituting heparin with another anticoagulant is that the potential benefit of stopping heparin (e.g., less antibody-induced heparin-dependent platelet activation) might be outweighed in some patients by a rebound in thrombin generation following loss of heparin's anticoagulant action. Moreover, as discussed later, HIT antibodies sometimes can cause platelet activation even in the absence of pharmacologic heparin. Not infrequently, patients in whom heparin administration has been...

HIT is a strong, independent risk factor for venous and arterial thrombosis (Warkentin et al., 1995, 2003). HIT can be complicated by thrombosis in several ways (1) a preceding thrombosis, leading to the heparin treatment that caused HIT (this is usually not considered to be HIT-associated thrombosis) (2) new, progressive, or recurrent thrombosis resulting from HIT itself or (3) both reasons. The relationship between thrombocytopenia and thrombosis in HIT is variable thrombosis can both precede (or coincide with) the onset of thrombocytopenia or thrombosis can occur several days (or even a few weeks) later (Warkentin and Kelton, 1996 Greinacher et al., 2005).

For venous thrombosis without anticoagulation in a patient at very high bleeding risk. Thrombocytopenia itself should not be considered a contraindication to anticoagulation in patients with HIT, as petechiae and other spontaneous hemor-rhagic manifestations are not usually seen in these patients (see Chapter 2). However, if the platelet count is less than 20 X 109 L and bleeding signs, but not thrombosis, are observed, then alternative diagnoses such as posttransfusion purpura or other drug-dependent immune thrombocytopenic disorders should be considered (Kiefel, 2004). Recommendation. Alternative therapeutic-dose anticoagulation with an appropriate anticoagulant, such as danaparoid, lepirudin, or argatroban, should be considered in patients strongly suspected (or confirmed) to have HIT even in the absence of symptomatic thrombosis. Anticoagulation should be continued at least until recovery of the platelet counts to a stable plateau (grade 1C). It is uncertain whether...

Acute HIT by itself is not an indication for longer-term anticoagulation (i.e., 3-6 mo). However, HIT-associated thrombosis, or the underlying disease itself, often is. For longer-term control of thrombosis, oral anticoagulants of the coumarin class (e.g., warfarin or phenprocoumon) are the treatment of choice. However, as discussed subsequently, it is important that coumarin therapy be delayed until there has been substantial recovery in the platelet count. Another option is to avoid coumarin therapy completely, e.g., a patient can be anticoagulated with danaparoid (e.g. 1500 U sc t.i.d. for 4 wk, followed by 1500 U sc b.i.d.). Some physicians have transitioned patients from DTI therapy to sc fondaparinux following platelet count recovery.

In a patient with an intermediate probability for HIT (e.g., 4T's score of 4 or 5), who has an alternative explanation for thrombocytopenia and who does not require therapeutic-dose anticoagulation for other reasons, we suggest alternative anticoagulation in prophylactic, rather than in therapeutic, doses (Grade 2C).

Treatment of HIT with LMWH is frequently unsuccessful. Of eight consecutive HIT patients who received LMWH, thrombocytopenia persisted in all, and new thromboembolic events occurred in two patients (Greinacher et al., 1992). After LMWH became available in North America, a similar experience was observed in seven HIT patients treated with LMWH (Warkentin, 1997). Another study has also shown a relatively high risk of adverse outcomes of treating HIT with LMWH (Ranze et al., 2000).

To progress to involve even the microvasculature, leading to coumarin-induced venous limb gangrene. This syndrome appears to result from a transient disturbance in procoagulant-anticoagulant balance increased thrombin generation associated with HIT remains high during early warfarin treatment, while simultaneously there is severe, acquired deficiency in the natural anticoagulant protein C. Although high doses of oral anticoagulants may be more likely to cause this syndrome, even relatively low doses that produce a rise in the INR (especially to &gt 4.0) can cause limb gangrene in some patients, particularly in patients with severe HIT-associated hypercoagulability and overt (decompensated) DIC. Thus, warfarin and phenpro-coumon should always be given in combination with an agent that reduces thrombin generation in patients with acute HIT, and must only be started once the acute HIT has largely subsided, as judged by substantial recovery of the platelet count (in general, &gt 150 X 109...

Usually there is no need to treat thrombocytopenia with platelet transfusions, as patients with HIT rarely bleed spontaneously. Indeed, platelet transfusions should be avoided because the transfused platelets can be activated by the same immune mechanisms as the patient's own platelets. Anecdotal experience describes throm-botic events soon after platelet transfusions given to patients with acute HIT (Babcock et al., 1976 Cimo et al., 1979). Several consensus conferences (Contreras, 1998 Hirsh et al., 2001 British Committee for Standards in Haematology, 2003 Warkentin and Greinacher, 2004) stated that thrombotic thrombocytopenic purpura (TTP) and HIT are two disorders in which prophylactic platelet transfusions are not recommended because of the risk of precipitating thrombosis.

By the manufacturer (Magnani, 1993, 1997). From 1981 to 1997, over 750 patients were treated under this program for the various indications listed earlier (Ortel and Chong, 1998). The duration of treatment ranged from 1 day to 3.5 yr, and the post-treatment follow-up was 3 mo. Interim, updated reports of this program have been published (Chong and Magnani, 1992 Magnani, 1993, 1997). The overall success rate, defined as platelet count recovery without new, progressive, or recurrent thrombosis during the danaparoid treatment period, or thrombotic death during 3 mo follow-up, and the absence of any adverse effect necessitating treatment cessation, has been over 90 , as judged by the local physician-investigators. However, as this definition does not include non-thrombotic death, the overall mortality observed in the program was 18 , including deaths during the post-treatment follow-up. Most patients in this program received danaparoid for the treatment of acute thromboembolism, often in...

Many danaparoid-treated HIT patients also receive overlapping warfarin treatment, since oral anticoagulants are usually preferred when at least 3-6 mo of further anticoagulation is indicated because of venous or arterial thromboembolism. However, it generally takes at least 5 days for warfarin to achieve a therapeutic effect (Harrison et al., 1997). Although warfarin likely can be started safely at the beginning of danaparoid treatment in most patients with HIT-associated thrombosis, it is prudent to delay start of warfarin until the thrombotic process is controlled and substantial resolution of the thrombocytopenia has occurred (usually, to a platelet count &gt 150 X 109 L). This caveat is based on the observation that warfarin can aggravate the thrombotic process during the first few days of its administration by reducing levels of the natural anticoagulant protein C, particularly when thrombin generation is high (Warkentin, 1996a Warkentin et al., 1997 Potzsch et al., 1996) (see...

It is important to incorporate clinical information into the interpretation of any laboratory result for HIT. This is because thrombocytopenia, whether or not caused by HIT, is common in hospitalized patients receiving heparin, and because nonpathogenic HIT antibodies are often detected by sensitive assays in patients who have received heparin for 5 or more days. Several clinical scoring methods have been described to help estimate the probability of HIT independently of the HIT antibody test results (Greinacher et al., 1994a Pouplard et al., 1997 Warkentin, 2003a Warkentin and Heddle, 2003 Lo et al., 2006). Some include assessing the platelet count recovery upon stopping heparin, and so may be more useful when reviewing a case after its clinical evolution. Chapter 2 provides an example of one scoring system to estimate the pretest probability of HIT that can be applied at the time of initial diagnostic assessment.

Were the same as those in non-pregnant women for the same indications. In 24 pregnancies (75 ) carried to term, normal babies were delivered either vaginally or by caesarian section, although in some a maternal adverse event (usually associated with a placental abnormality) occurred. In eight pregnancies, danapar-oid was stopped prematurely. In two patients, this was because of successful short-term use (no further follow-up). Early fetal death occurred in three pregnancies, two in association with the maternal antiphospholipid syndrome, the other a therapeutic abortion necessitated by a maternal amputation due to thrombosis extension in the second trimester. In two pregnancies, major bleeds occurred, one due to placental abruption (fatal bleeding followed caesarian section in a Jehovah's Witness) after 24 wk of problem-free danaparoid use, and one due to placenta previa with fatal cardiopulmonary complications after caesarian section. One pregnancy was complicated by the onset of...

The in vitro cross-reactivity of the HIT antibodies with danaparoid does not appear to be usually clinically significant. Newman et al. (1998) investigated the clinical significance of in vitro cross-reactivity in 21 patients treated with danapar-oid. The eight patients who tested positive for cross-reactivity by the fluid-phase EIA, but negative by the 14C serotonin-release washed platelet assay, recovered with resolution of their thrombocytopenia and thrombosis, in a fashion similar to the 11 patients who did not manifest in vitro danaparoid cross-reactivity in either assay. Two patients tested positive in both assays in one patient, both thrombocy-topenia and pulmonary embolism resolved during danaparoid treatment. However, in the other patient, thrombocytopenia and extensive thrombosis persisted despite danaparoid therapy, although it was unclear whether this unusual patient course represented a specific danaparoid treatment failure (the patient's subsequent clinical course was...

Long-term treatment of HIT patients often involves a transition from DTI to oral anticoagulation. Initiation of the transition to vitamin K antagonist (coumarin) therapy should begin only after the platelet count has substantially recovered (preferably, &gt 150 x 109 L), with a minimum of 5 days of overlapping therapy with an alternative anticoagulant, and with the last 2 days stably within the target therapeutic range (Warkentin and Greinacher, 2004). In patients with deep vein thrombosis (DVT) associated with acute HIT, the use of vitamin K antagonist can be associated with venous limb gangrene, which typically occurs when this anticoagulant is used alone for treatment of HIT, or when overlapping therapy with DTIs is not managed appropriately, e.g., early initiation of coumarin and premature discontinuation of the DTI.

An abrupt fall in the platelet count invariably accompanies these reactions. However, the platelet count drop is often transient (Warkentin et al., 2005b). Thus, physicians should determine the platelet count immediately on suspecting the diagnosis and test for HIT antibodies. Heparin must be discontinued, as further use can lead to fatal complications (Ling and Warkentin, 1998). Any inflammatory, cardiopulmonary, or other unexpected acute event that begins 5-30 min after an intravenous heparin bolus should be considered acute HIT unless proved otherwise. The postbolus platelet count should be measured promptly and compared with prebolus levels, because the platelet count fall is abrupt and often transient. Timing onset 5-30 min after intravenous heparin bolus Clinical context recent use of heparin (past 5-100 days) Laboratory features abrupt, reversible fall in the platelet count Signs and symptoms similarities between ASR and the administration of ADP in humans, including acute...

Because of the often critical condition of the patient population under study, the rate of deaths observed for both DTIs is not likely to be solely attributable to treatment failure and may vary considerably with different patient populations. As the argatroban trials included many patients who most likely did not have HIT, the death rate associated with HIT might have been overestimated, as non-HIT patients with a decrease of platelet count are often very sick (e.g., septicemia, DIC). Death rates were 14.3 (meta-analysis) and 12.3 (DMP) for patients with isolated HIT treated with lepirudin, but 18.1 and 23.1 in those treated in the two argatroban trials. In patients with HIT complicated by thrombosis, death rates with lepirudin were 11.9 (meta-analysis) and 10.9 (DMP), compared with 18.0 and 23.1 in the argatroban trials. The major conclusions of these comparisons are (1) HIT patients seem to benefit from a longer treatment period with an alternative anticoagulant, with 10 days...

Although rare in children, HIT is important in the differential diagnosis of thrombocytopenia or unexplained thrombosis in the presence of heparin administration (Ranze et al., 1999 Klenner et al., 2004). Because of the rarity of HIT and its clinical heterogeneity in pediatric patients, it is difficult to design a standardized dosage protocol for lepirudin. Accordingly, current therapeutic recommendations are based on anecdotal experience. Given that children usually have

A subgroup analysis of the prospective studies of argatroban in HIT identified 36 patients with a history of serologically confirmed HIT who had fully recovered from their initial episode of HIT, had a normal platelet count, and had no exposure to heparin or other parenteral anticoagulants (except argatroban) during their hospitalization (Matthai et al., 2005). Each patient required acute anticoagulation, most often for venous thromboembolism or acute coronary syndrome, and 12 had previously received argatroban. All evaluable patients were successfully anticoagulated. No one had a major bleeding or a new thromboembolic event. There were no adverse events related to reexposure.

Bivalirudin has also been studied in a rat model of endotoxemia and found to increase survival rate in one (but not the other) study (Cicala et al., 1995 Itoh et al., 1996). Bivalirudin reduced endotoxin-induced thrombocytopenia, leukope-nia, and fibrinogen consumption, suggesting a possible future therapeutic role in sepsis (Cicala et al., 1995).

The first published case of fondaparinux use in a patient with HIT was by Dr. Elbio D'Amico et al. (2003). A patient with paroxysmal nocturnal hemo-globinuria and Budd-Chiari syndrome developed HIT following administration of LMWH (dalteparin 5000IU sc q12h). The patient experienced spontaneous platelet count recovery, and received thrombolytic therapy. While receiving prophylactic doses of fondaparinux, the platelet count remained unchanged and the patient was transitioned uneventfully to oral anticoagulant therapy. treat HIT (Table 3). The case series involved 38 patients with HIT who were treated with fondaparinux at the Massachusetts General Hospital (MGH) between January 1, 2002, and August 1, 2004 (Table 3). This series represents two cohorts of patients treated either with fondaparinux after initial treatment with a DTI (n 17) or receiving fondaparinux for the initial treatment of HIT (n 21). Platelet count recovery data from the MGH series are presented in Figure 3,...

FIGURE 3 Twenty-two patients with HIT were treated with fondaparinux at (or near) the platelet count nadir following exposure to UFH or LMWH. Platelet count recovery is illustrated by this graph, which compares mean platelet counts for the population. Platelet data have been normalized by subtracting the individual value of the patient's platelet count at first administration of fondaparinux from each preceding and subsequent measurement. Error bars represent one standard deviation from the mean. Abbreviations UFH, unfractionated heparin LMWH, low molecular weight heparin HIT, heparin-induced thrombocytopenia. FIGURE 3 Twenty-two patients with HIT were treated with fondaparinux at (or near) the platelet count nadir following exposure to UFH or LMWH. Platelet count recovery is illustrated by this graph, which compares mean platelet counts for the population. Platelet data have been normalized by subtracting the individual value of the patient's platelet count at first administration of...

The diagnosis of HIT and respective management decisions should be primarily based on clinical criteria (Lewis et al., 1997). A further consideration in HD patients is that the procedure of HD itself is associated with a relative decrease in platelet count, even when so-called biocompatible dialyzer membranes are used (Beijering et al., 1997 Schmitt et al., 1987). Furthermore, the fall in platelet count in HD patients developing HIT may be only moderate (Matsuo et al., 1997). Severe skin necrosis, even in the presence of normal platelet counts, has been reported in association with the presence of HIT antibodies in patients after both short- and long-term HD (Bredlich et al., 1997 Leblanc et al., 1994). Rarely, patients can develop HIT after years of regular long-term maintenance HD. Tholl et al. (1997) reported a patient who developed HIT following surgery after 9 yr of long-term intermittent HD performed with UFH. In this patient, an anaphylactic reaction to heparin, accompanied by...

LMWH is not recommended as an alternative anticoagulant for managing acute HIT. In vitro tests for HIT antibodies show a high degree of cross-reactivity between UFH and LMWH (Greinacher et al., 1992b Vun et al., 1996). Furthermore, in vivo cross-reactivity manifesting as persistent or recurrent thrombocytopenia or thrombosis during LMWH treatment of HIT appears to be common (Greinacher et al., 1992a Horellou et al., 1984 Roussi et al., 1984). Because non-heparin anticoagulants are available, LMWH probably should not be used even if in vitro cross-reactivity is reported to be negative.

HIT antibodies potentially cross-react with danaparoid. Although the respective clinical risk has been claimed to be less than 5 (Warkentin et al., 1998 Magnani and Gallus, 2006), individual patients, nevertheless, may be threatened if this condition occurs. As positive in vitro cross-reactivity is of uncertain clinical significance (Warkentin, 1996 Wilde and Markham, 1997 Newman et al., 1998), attention should focus on platelet count monitoring. A further fall in platelet count, or new fibrin deposits and clot formation within the extracorporeal circuit after application of danaparoid, may indicate clinically relevant cross-reactivity. To differentiate in vivo cross-reactivity from under-anticoagulation owing to insufficient dosage, determination of antifactor Xa levels and HIT antibody cross-reactivity studies are needed.

An intriguing option for patients with a history of HIT, but in whom HIT antibodies can no longer be detected, is to consider reexposure to UFH for CPB, and to avoid heparin completely both before surgery (e.g., at heart catheterization) and in the postoperative period. This approach has been used successfully (Makhoul et al., 1987 Potzsch et al., 2000 Selleng et al., 2001 Warkentin and Kelton, 2001), and is based on the following rationale. First, HIT antibodies are transient, and are usually not detectable after several weeks or a few months following an episode of HIT (see Chapter 2). Thus, no immediate problems would be expected in a patient without residual HIT antibodies. Second, it appears that a minimum of 5 days are required before clinically significant levels of HIT antibodies are generated following any episode of heparin treatment (Warkentin and Kelton, 2001). In the event that a recurrent immune response to PF4-heparin is induced by reexposure to heparin during CPB, it...

Skouri et al. (2006) performed a prospective study in the pediatric hemodialysis unit, evaluating 38 children between 1 and 16 yr of age (mean, 10.45 yr) undergoing chronic hemodialysis thrice weekly. Patients received i.v. UFH as a single bolus (70 IU kg body weight). Plasma samples were tested for antibodies by PF4 heparin-EIA and by a functional assay utilizing washed platelets, the heparin-induced platelet activation assay (HIPA). Of 38 patients, nine patients (21 ) tested positive by EIA and or HIPA, but none had thrombocytopenia or clinical thrombosis. Sequential EIAs performed every 3 mo in seven of the eight patients with antibodies detected by EIA showed gradual reductions in antibody levels in six children, with a persistently positive EIA seen in only one patient at 1-yr follow-up.

Numerous case reports describe the occurrence of new or recurrent thromboem-bolic events during continued or repeated use of heparin in adult patients with acute HIT. Further, thrombocytopenia usually persists if heparin is not stopped. Thus, all heparin should be discontinued in patients strongly suspected of having HIT, including heparin flushes, heparin-coated catheters, and heparin-containing blood products (Severn et al., 2002b) (see Chapter 12). As in adults, low molecular weight heparin (LMWH) should not be used to treat acute HIT in children (see Chapter 12).

The syndrome of delayed-onset HIT was elucidated a few years ago, and is now increasingly recognized around the world (Warkentin and Kelton, 2001b Rice et al., 2002). The patients have been off heparin for a few days or more, often recuperating at home from a benign hospital course that included heparin exposure, then they return to hospital with an arterial or venous thrombotic event. Upon return, the platelet count is often (although not necessarily) low. These people are often given heparin for their presenting thrombosis, which invariably leads to an abrupt fall in platelet count, frequently clinical deterioration, and substantial mortality. Invariably, there are high-titer antibodies against PF4-heparin complexes. The message to emergency room doctors, intensivists, and hospitalists is to consider the possibility of delayed-onset HIT and not to initiate heparin reflex-ively when a recently hospitalized patient returns with thrombosis. Of note, the U.S. Food and Drug...

The time just after heparin is stopped may be the most dangerous for the emergence of thromboemboli, because heparin may be exerting some protective anticoagulant effect at the same time it is feeding a prothrombotic maelstrom. The protocol for the lepirudin registration trials in Europe called for heparin to be stopped when HIT is suspected, but lepirudin was initiated only after obtaining positive serologic results a 6 per day thrombosis event rate was observed while physicians awaited the test results (Greinacher et al., 2000). The initial suspicion for HIT depends on clinical features, such as the 4 T's (Thrombocytopenia, Timing, Thrombosis, oTher causes of thrombocytopenia unlikely) (Lo et al., 2006) when HIT is reasonably suspected, an alternative anticoagulant should be initiated, and the results of serologic tests considered later.

To minimize the risk of coumarin necrosis in a patient with acute HIT, vitamin K antagonist (coumarin) therapy should be delayed until the patient is adequately anticoagulated with a rapidly acting parenteral anticoagulant, and not until there has been substantial platelet count recovery (at least &gt 150 X 109 L). The vitamin K antagonist should be started in low maintenance doses (e.g., &lt 5 mg warfarin), with at least 5 days of overlap with the parenteral anticoagulant (including at least 2 days in the target-therapeutic range), and the parenteral anticoagulant should not be stopped until the platelet count has reached a stable plateau (Grade 1C).

If HIT, consider anticoagulating until platelet count recovery, even if no thrombosis apparent ( coumarink) k Do not begin coumarin until there is substantial recovery of platelet count (usually, &gt 150) begin coumarin in low, maintenance doses only, with minimum 4-5 day overlap with alternative anticoagulant stop coumarin when INR therapeutic at least 2 days

Although first reported in 1973, immune heparin-induced thrombocytopenia (HIT) remains one of the most potentially devastating and frequent adverse drug reactions encountered by physicians. This Fourth Edition reinforces its standing as the leading guide to the accurate diagnosis and management of HIT by identifying key signs and symptoms of this disorder and providing clear intervention strategies, including detailed information on the use of alternative anticoagulants to manage these critical circumstances.

The role of EC-reactive antibodies was also explored in an animal model that simulates certain aspects of HIT (Blank et al., 1997). Mice injected with IgG fractions obtained from HIT patients developed anti-idiotypic antibodies that recognized complexes between hPF4 and heparin. Furthermore, the anti-idiotypic antibodies competed with the immunizing antibodies for binding to the antigenic complex. These effects were not noted when antibodies obtained from mice immunized with control IgG were studied. Additionally, mice immunized with HIT-IgG developed thrombocytopenia when exposed to heparin. Affinity-purified anti-PF4-heparin antibodies bound to murine endothelioma cells in the presence of PF4, but not b2GPI. Of interest, immunized mice did not develop overt thrombi on exposure to heparin, possibly because of insufficient circulating PF4, intrinsic differences in the balance between the procoagulant and fibrinolytic systems compared with humans, or differences in signal transduction...

Monocytes and macrophages possess several different classes of FcyR (Table 1), and thus may play a part in influencing the frequency and severity of both thrombocytopenia and thrombosis in HIT. One role, discussed in the previous section, involves their potential to influence the balance between platelet activation and reticuloendothelial-mediated platelet clearance in HIT. Another function recently proposed for monocytes is that of contributing to the procoagulant state in HIT (a role posited previously for endothelial cells) (see Chapter 9). Pouplard and colleagues (2001) found that by adding HIT-IgG and PF4 (or PF4-H) directly to isolated monocytes or to whole blood, the monocytes produced TF, an effect that could be inhibited by high concentrations of heparin. Arepally and Mayer (2001) found that monocytes expressed surface TF when incubated with PF4 in the presence of either HIT-IgG or the HIT-mimicking murine monoclonal antibody, KKO. Because monocytes express sulfated...

Vascular surgery is often needed to salvage an ischemic limb threatened by HIT-associated acute arterial thromboembolism involving large arteries (Sobel et al., 1988). When performing vascular surgery during acute HIT, it is appropriate to maintain anticoagulation at least in the lower therapeutic range, if possible, before, during, and after surgery, until platelet count recovery. In patients with latent HIT (i.e., no longer thrombocytopenic, but with clinically significant levels of HIT antibodies still present), the intensity of anticoagulation depends on the perceived risk of vessel (or graft) occlusion. In patients at high risk of occlusion (e.g., surgery involving below-knee vessels), the patient should be therapeutically anticoagulated before vessel clamping (in addition to receiving intraoperative flushes with anticoagulant), with therapeutic anticoagulation maintained for several days after Recommendation. Surgical thromboembolectomy is an appropriate adjunctive treatment for...

Mucin-producing adenocarcinoma is an important cause of venous and arterial thrombosis that occurs in association with thrombocytopenia. In these patients, DIC is often the predominant explanation for the thrombocytopenia. The diagnosis is suggested by reduced fibrinogen levels (or prolonged thrombin time), elevated prothrombin time, and elevated cross-linked (D-dimer) fibrin degradation products (or a positive protamine sulfate paracoagulation test). Adenocarcinoma-associated DIC can strongly resemble HIT (Fig. 1). Typically, a patient presents with idiopathic deep vein thrombosis (DVT), sometimes with mild to moderate thrombocytopenia. During treatment with therapeutic-dose unfractionated or low molecular weight heparin (LMWH), the platelet count rises, FIGURE 1 Pseudo-HIT adenocarcinoma with thrombocytopenia and phlegmasia cerulea dolens after stopping administration of UFH. The late presentation of thrombocytopenia suggested HIT, prompting use of an alternative anticoagulant...

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